chr15-90749844-CTT-C

Variant names:

• chr15-90749844-CTT-C
• rs367543026
• NM_000057.4:c.581_582delTT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000057.4(BLM):​c.581_582delTT​(p.Phe194fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F194F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BLM NM_000057.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.867
• Publications: 2 publications found

Genes affected

BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]

BLM Gene-Disease associations (from GenCC):

• Bloom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-90749844-CTT-C is Pathogenic according to our data. Variant chr15-90749844-CTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 189032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.581_582delTT	p.Phe194fs	frameshift	Exon 3 of 22	NP_000048.1	P54132
	BLM	NM_001287246.2		c.581_582delTT	p.Phe194fs	frameshift	Exon 4 of 23	NP_001274175.1	P54132
	BLM	NM_001287247.2		c.581_582delTT	p.Phe194fs	frameshift	Exon 3 of 20	NP_001274176.1	H0YNU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.581_582delTT	p.Phe194fs	frameshift	Exon 3 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.581_582delTT	p.Phe194fs	frameshift	Exon 3 of 20	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.581_582delTT		non_coding_transcript_exon	Exon 3 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440708 Hom.: 0 AF XY: 0.00000280 AC XY: 2 AN XY: 714954

African (AFR) AF: 0.00 AC: 0 AN: 32252

American (AMR) AF: 0.00 AC: 0 AN: 40658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 82852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102782

Other (OTH) AF: 0.00 AC: 0 AN: 59376

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Bloom syndrome (4)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.87
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs367543026; hg19: chr15-91293074;